Carbamic acid esters as inhibitors of factor xa

ABSTRACT

Novel compounds of the formula I  
                 
 
     in which  
     R, R 1  and R 2  are as defined in Patent claim 1,  
     are inhibitors of coagulation factor Xa and can be employed for the prophylaxis and/or therapy of thromboembolic illnesses.

[0001] The invention relates to compounds of the formula I

[0002] in which

[0003] R is —CO—N═C(NH₂)₂, —NH—C(═NH)—NH₂ or —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —OCOO(CH₂)_(n)NAA′, —COO(CH₂)_(n)NAA′, —OCOO(CH₂)_(m)-Het, —COO(CH₂)_(m)-Het, —CO—CAA′—R³, —COO—CAA′—R³, COOA, COSA, COOAr or COOAr′ or by a conventional amino-protecting group,

[0004] R¹ is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH₂ groups may be replaced by O or S atoms, or is Ar, Ar′ or X,

[0005] R² is phenyl which is monosubstituted by S(O)_(p)A, S(O)_(p)NHA, CF₃, COOA, CH₂NHA, CN or OA,

[0006] R³

[0007] Ar is phenyl or naphthyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A, OA, NAA′, NO₂, CF₃, CN, Hal, NHCOA, COOA, CONAA′, S(O)_(p)A or S(O)_(p)NAA′,

[0008] Ar′ is —(CH₂)_(n)—Ar,

[0009] A and A′ are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-20 carbon atoms,

[0010] Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having 1 to 4 N, O and/or S atoms, bonded via N or C, which may be unsubstituted or substituted by A,

[0011] X is —(CH₂)_(n)—Y,

[0012] Y is COOA or

[0013] Hal is F, Cl, Br or I,

[0014] m is 0 or 1,

[0015] n is 1, 2, 3, 4, 5 or 6, and

[0016] p 0, 1 or 2,

[0017] and their pharmaceutically tolerated salts and solvates.

[0018] The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, for example alcoholates, of these compounds.

[0019] The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

[0020] It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties while being well tolerated. In particular, they exhibit factor Xa-inhibiting properties and can therefore be employed for combating and preventing thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.

[0021] The compounds of the formula I according to the invention may furthermore be inhibitors of coagulation factor VIIa, factor IXa and thrombin in the blood coagulation cascade.

[0022] Aromatic amidine derivatives having an antithrombotic action are disclosed, for example, in EP 0 540 051 B1. Cyclic guanidines for the treatment of thromboembolic illnesses are described, for example, in WO 97/08165. Aromatic heterocyclic compounds having factor Xa-inhibitory activity are disclosed, for example, in WO 96/10022. Substituted N-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679. Other compounds are described in WO 97/30971 or WO 99/10361.

[0023] The antithrombotic and anticoagulant effect of the compounds according to the invention is attributed to the inhibitory action against activated coagulation protease, known by the name factor Xa, or to the inhibition of other activated serine proteases, such as factor VIIa, factor IXa or thrombin.

[0024] Factor Xa is one of the proteases involved in the complex process of blood coagulation. Factor Xa catalyses the conversion of prothrombin into thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which, after crosslinking, make an elementary contribution to thrombus formation. Activation of thrombin may result in the occurrence of thromboembolic illnesses. However, inhibition of thrombin may inhibit the fibrin formation involved in thrombus formation. The inhibition of thrombin can be measured, for example, by the method of G. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

[0025] Inhibition of factor Xa can thus prevent the formation of thrombin.

[0026] The compounds of the formula I according to the invention and their salts engage in the blood coagulation process by inhibiting factor Xa and thus inhibit the formation of thrombuses.

[0027] The inhibition of factor Xa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A suitable method is described, for example, by J. Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

[0028] The inhibition of factor Xa can be measured, for example, by the method of T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

[0029] Coagulation factor VIIa initiates the extrinsic part of the coagulation cascade after binding to tissue factor and contributes to the activation of factor X to give factor Xa. Inhibition of factor Vila thus prevents the formation of factor Xa and thus subsequent thrombin formation.

[0030] The inhibition of factor VIIa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A conventional method for the measurement of the inhibition of factor VIIa is described, for example, by H. F. Ronning et al. in Thrombosis Research 1996, 84, 73-81.

[0031] Coagulation factor IXa is generated in the intrinsic coagulation cascade and is likewise involved in the activation of factor X to give factor Xa. Inhibition of factor IXa can therefore prevent the formation of factor Xa in a different way.

[0032] The inhibition of factor IXa by the compounds according to the invention and the measurement of the anticoagulant and antithrombotic activity can be determined by conventional in-vitro or in-vivo methods. A suitable method is described, for example, by J. Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.

[0033] The invention relates to the compounds of the formula I according to claims 1 and 2 and their physiologically acceptable salts and solvates as medicaments.

[0034] The compounds of the formula I can be employed as medicament active ingredients in human and veterinary medicine, in particular for combating and preventing thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.

[0035] The invention therefore also relates to the said medicaments as inhibitors of coagulation factor Xa and to this medicament for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.

[0036] The invention relates to the compounds of the formula I and their salts and to a process for the preparation of compounds of the formula I according to claim 1 in which R is amidino, and their salts, characterized in that

[0037] a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent

[0038] and/or

[0039] b) a base or acid of the formula I is converted into one of its salts.

[0040] For all radicals which occur more than once, their meanings are independent of one another.

[0041] The abbreviations have the following meanings below: Ac acetyl BOC tert-butoxycarbonyl CBZ or Z benzyloxycarbonyl DAPECI N-(3-dimethylaminopropyl)-N-ethylcarbodiimide DCCI dicyclohexylcarbodlimide DMAP dimethylaminopyridine DMF dimethylformamide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl HONSu N-hydroxysuccinimide OBut tert-butyl ester Oct octanoyl OMe methyl ester OEt ethyl ester RT room temperature THF tetrahydrofuran TFA trifluoroacetic acid Trt trityl (triphenylmethyl).

[0042] Above and below, the radicals and parameters R, R¹, R², R³, Ar, Ar′, A, A′, Het, X, Y, n, m and p have the meanings indicated under the formula I, unless expressly stated otherwise.

[0043] Alkyl is unbranched (linear) or branched, and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Alkyl is preferably methyl, further-more ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, further-more also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermore preferably, for example, trifluoromethyl.

[0044] A is very particularly preferably alkyl having 1-6 carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

[0045] Cyclic alkyl or cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0046] Hal is preferably F, Cl or Br, but also I.

[0047] Ar is phenyl or naphthyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A, OA, NAA′, NO₂, CF₃, CN, Hal, NHCOA, COOA, CONAA′, S(O)_(p)A or S(O)_(p)NAA′.

[0048] Preferred substituents for phenyl or naphthyl are, for example, methyl, ethyl, propyl, butyl, OH, methoxy, ethoxy, propoxy, butoxy, amino, methyl-amino, dimethylamino, ethylamino, diethylamino, nitro, trifluoromethyl, fluorine, chlorine, acetamido, methoxycarbonyl, ethoxycarbonyl, amino-carbonyl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, tert-butylsulfonamido, tert-butylaminosulfonyl, dimethylsulfonamido, phenylsulfonamido, carboxyl, dimethylamino-carbonyl, phenylaminocarbonyl, acetyl, propionyl, benzoyl, methylsulfonyl or phenylsulfonyl.

[0049] Ar is particularly preferably, for example, unsubstituted phenyl or phenyl which is monosubstituted by SO₂NH₂, SO₂CH₃, fluorine or alkoxy, such as, for example, methoxy.

[0050] Ar′ is —(CH₂)_(n)—Ar, preferably benzyl which is unsubstituted or mono-substituted, disubstituted or trisubstituted by fluorine and/or chlorine.

[0051] Y is preferably, for example, methoxycarbonyl, ethoxycarbonyl or 1-methyltetrazol-5-yl.

[0052] In X, n is preferably, for example, 1 or 2.

[0053] Het is preferably, for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-4-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazo-linyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5-yl.

[0054] The heterocyclic radicals may also be partially or fully hydrogenated. Het can thus, for example, also be 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermore preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxomethylenedioxy)phenyl or alternatively 3,4-dihydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-oxofuranyl.

[0055] Het is particularly preferably, for example, furyl, thienyl, thiazolyl, imidazolyl, 2,1,3-benzothiadiazolyl, oxazolyl, pyridyl, indolyl, 1-methyl-piperidinyl, piperidinyl or pyrrolidinyl, very particularly preferably pyridyl, 1-methylpiperidin-4-yl or piperidin-4-yl.

[0056] R is preferably, for example, amidino, N-methoxycarbonylamidino, N-ethoxycarbonylamidino, N-(2,2,2-trichloroethoxycarbonyl)amidino, N-ethylthiocarbonylamidino, N-benzyloxycarbonylamidino, N-phenoxycarbonylamidino, N-(4-fluorophenoxycarbonyl)amidino, N-(4-methoxy-phenylthiocarbonyl)amidino, N-[CH₃CO—O—CH(CH₃)—O—CO]-amidino=N-acetoxyethoxycarbonylamidino, N-ethoxycarbonyloxyamidino, N—(N,N-eiethylaminoethoxycarbonyl)amidino, N-[(1-methylpiperidin-4-yl)-oxy-carbonyl]amidino or N-[(pyridin-2-yl)ethoxycarbonyl]amidino.

[0057] R¹ is preferably, for example, phenyl, benzyl, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, pentyl, pent-3-yl, cyclohexylmethyl, 4-fluorobenzyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, (1-methyltetrazol-5-yl)ethyl, methoxyethyl, methoxymethyl or methoxybutyl.

[0058] R² is preferably, for example, phenyl which is monosubstituted by SO₂NH₂ or SO₂Me.

[0059] The compounds of the formula I may have one or more chiral centres and therefore exist in various stereoisomeric forms. The formula I covers all these forms.

[0060] Accordingly, the invention relates in particular to the compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds may be expressed by the following sub-formulae Ia to Ih, which conform to the formula I and in which the radicals not designated in greater detail have the meaning indicated under the formula I, but in which

[0061] in Ia R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0062] in Ib R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0063] R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X;

[0064] in Ic R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0065] R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X,

[0066] R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA;

[0067] in Id R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0068] R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X,

[0069] R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA,

[0070] R³ is —CCl₃ or —O(C═O)A;

[0071] in Ie R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0072] R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X,

[0073] R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA,

[0074] R³ is —CCl₃ or —O(C═O)A,

[0075] Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂;

[0076] in If R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0077] R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X,

[0078] R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA,

[0079] R³ is —CCl₃ or —O(C═O)A,

[0080] Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂,

[0081] Ar′ is benzyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by fluorine;

[0082] in Ig R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0083] R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X,

[0084] R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA,

[0085] R³ is —CCl₃ or —O(C═O)A,

[0086] Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂,

[0087] Ar′ is benzyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by fluorine,

[0088] A and A′ are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-8 carbon atoms;

[0089] in Ih R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

[0090] R′ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X,

[0091] R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA,

[0092] R³ is —CCl₃ or —O(C═O)A,

[0093] Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂,

[0094] Ar′ is benzyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by fluorine,

[0095] A and A′ are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-8 carbon atoms,

[0096] Het is a monocyclic saturated or aromatic heterocyclic radical having 1 or 2 N and/or O atoms.

[0097] The compounds of the formula I and also the starting materials for the preparation are, in addition, prepared by methods known per se, as described in the literature (for example in the standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), to be precise under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.

[0098] If desired, the starting materials can also be formed in situ so that they are not isolated from the reaction mixture, but instead are immediately converted further into the compounds of the formula I.

[0099] Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent.

[0100] Preferred starting materials for the solvolyis or hydrogenolysis are those which conform to the formula I, but contain corresponding protected amino and/or hydroxyl groups instead of one or more free amino and/or hydroxyl groups, preferably those which carry an amino-protecting group instead of an H atom bonded to an N atom, in particular those which carry an R′—N group, in which R′ is an amino-protecting group, instead of an HN group, and/or those which carry an hydroxyl-protecting group instead of the H atom of an hydroxyl group, for example those which conform to the formula I, but carry a —COOR″ group, in which R″ is an hydroxyl-protecting group, instead of a —COOH group.

[0101] Preferred starting materials are also the oxadiazole derivatives which can be converted into the corresponding amidino compounds.

[0102] The liberation of the amidino group from its oxadiazole derivative can be carried out, for example, by treatment with hydrogen in the presence of a catalyst (for example water-moist Raney nickel). Suitable solvents are those indicated below, in particular alcohols, such as methanol or ethanol, organic acids, such as acetic acid or propionic acid, or mixtures thereof. The hydrogenolysis is generally carried out at temperatures between about 0 and 100° and pressures between about 1 and 200 bar, preferably at 20-30° (room temperature) and 1-10 bar.

[0103] The oxadiazole group is introduced, for example, by reaction of the cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate, chloroformates, N,N′-carbonyldiimidazole or acetic anhydride.

[0104] It is also possible for a plurality of—identical or different—protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protecting groups present are different from one another, they can in many cases be cleaved off selectively.

[0105] The term “amino-protecting group” is known in general terms and relates to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easy to remove after the desired chemical reaction has been carried out elsewhere in the molecule. Typical of such groups are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size is furthermore not crucial; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term “acyl group” is to be understood in the broadest sense in connection with the present process. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl, such as acetyl, propionyl and butyryl; aralkanoyl, such as phenylacetyl; aroyl, such as benzoyl and toluyl; aryloxyalkanoyl, such as POA; alkoxycarbonyl, such as methoxy-carbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butoxy-carbonyl) and 2-iodoethoxycarbonyl; aralkoxycarbonyl, such as CBZ (“carbobenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; and aryl-sulfonyl, such as Mtr. Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

[0106] The compounds of the formula I are liberated from their functional derivatives—depending on the protecting group used—for example using strong acids, advantageously using TFA or perchloric acid, but also using other strong inorganic acids, such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids, such as trichloroacetic acid, or sulfonic acids, such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but is not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids, such as acetic acid, ethers, such as tetrahydrofuran or dioxane, amides, such as DMF, halogenated hydrocarbons, such as dichloromethane, furthermore also alcohols, such as methanol, ethanol or isopropanol, and water. Mixtures of the above-mentioned solvents are furthermore suitable. TFA is preferably used in excess without addition of a further solvent, and perchloric acid is preferably used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50°, preferably between 15 and 30° (room temperature).

[0107] The BOC, OBut and Mtr groups can, for example, preferably be cleaved off using TFA in dichloromethane or using approximately 3 to 5N HCl in dioxane at 15-30°, and the FMOC group can be cleaved off using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30°.

[0108] Protecting groups which can be removed hydrogenolytically (for example CBZ, benzyl or the liberation of the amidino group from its oxadiazole derivative) can be cleaved off, for example, by treatment with hydrogen in the presence of a catalyst (for example a noble-metal catalyst, such as palladium, advantageously on a support, such as carbon). Suitable solvents here are those indicated above, in particular, for example, alcohols, such as methanol or ethanol, or amides, such as DMF. The hydrogenolysis is generally carried out at temperatures between about 0 and 100° and pressures between about 1 and 200 bar, preferably at 20-30° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds well, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in methanol/DMF at 20-30°.

[0109] Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, trifluoromethylbenzene, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, N-methylpyrrolidone (NMP) or dimethylformamide (DMF); nitrites, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids, such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents.

[0110] An SO₂NH₂ group, for example in R², is preferably employed in the form of its tert-butyl derivative. The tert-butyl group is cleaved off, for example, using TFA with or without addition of an inert solvent, preferably with addition of a small amount of anisole (1-10% by volume).

[0111] A cyano group is converted into an amidino group by reaction with, for example, hydroxylamine followed by reduction of the N-hydroxyamidine using hydrogen in the presence of a catalyst, such as, for example, Pd/C. In order to prepare an amidine of the formula I (for example Ar=phenyl which is monosubstituted by C(═NH)—NH₂), it is also possible to add ammonia onto a nitrile. The adduction is preferably carried out in a multistep process by, in a manner known per se, a) converting the nitrile into a thioamide using H₂S, converting the thioamide into the corresponding S-alkylimidothioester using an alkylating agent, for example CH₃I, and in turn reacting the thioester with NH₃ to give the amidine, b) converting the nitrile into the corresponding imidoester using an alcohol, for example ethanol, in the presence of HCl, and treating this ester with ammonia, or c) reacting the nitrile with lithium bis(trimethylsilyl)amide, and subsequently hydrolysing the product.

[0112] Some of the compounds of the formulae II, III, IV and V used as intermediates are known or can be prepared by conventional methods. The precursors of the compounds of the formula I are prepared, for example, by reacting compounds of the formula II

[0113] in which

[0114] R is CN, —CO—N═C(NH₂)₂, —NH—C(═NH)—NH₂ or —C(═NH)—NH₂ which is monosubstituted by OH, —OCOOA, —OCOO(CH₂)_(n)NAA′, —COO(CH₂)_(n)NAA′, —OCOO(CH₂)_(m)-Het, —COO(CH₂)_(m)-Het, —CO—CAA′-R³, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or by a conventional amino-protecting group,

[0115] and R¹ is as defined in claim 1,

[0116] with compounds of the formula III

[0117] in which R² is as defined in claim 1, but in which a free NH₂ or OH group is substituted by a protecting group.

[0118] The starting compounds of the formula II can be prepared by reacting the R¹-substituted amines of the formula IV

[0119] in which R and R′ are as defined under the formula II,

[0120] with compounds of the formula V

[0121] In the compounds of the formula V, L is preferably Cl, Br, I or a free or reactively modified OH group, such as, for example, an activated ester, an imidazolide or alkylsulfonyloxy having 1-6 carbon atoms (preferably methylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).

[0122] Preference is given to starting compounds of the formula II in which R is CN or 5-methyl-1,2,4-oxadiazolyl.

[0123] The reaction of the compounds of the formula II or IV with the components of the formula III or V respectively is carried out in a manner known per se, preferably in a protic or aprotic, polar or nonpolar inert organic solvent.

[0124] It is likewise advantageous to carry out the above reactions of the compounds of the formula IV with those of the formula V in the presence of a base or with an excess of the basic component. Examples are suitable solvents are preferably alkali metal or alkaline earth metal hydroxides, carbonates or alkoxides or organic bases, such as triethylamine, DMAP or pyridine, which are also used in excess and can then simultaneously serve as solvent.

[0125] Suitable inert solvents are, in particular, alcohols, such as methanol, ethanol, isopropanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, THF or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; nitriles, such as acetonitrile; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate; amides, such as hexamethylphosphoric triamide; sulfoxides, such as dimethyl sulfoxide (DMSO); chlorinated hydrocarbons, such as dichloromethane, chloroform, trichloroethylene, 1,2-dichloroethane or carbon tetrachloride; or hydrocarbons, such as benzene, toluene or xylene. Also suitable are mixtures of these solvents with one another.

[0126] Particularly suitable solvents are methanol, THF, dimethoxyethane, dioxane, water or mixtures which can be prepared therefrom. Suitable reaction temperatures are, for example, temperatures between 20° and the boiling point of the solvent. The reaction times are between 5 minutes and 30 hours. It is advantageous to employ an acid scavenger in the reaction. Suitable for this purpose are all types of bases which do not interfere with the reaction itself. Particularly suitable, however, is the use of inorganic bases, such as potassium carbonate, or of organic bases, such as triethylamine or pyridine.

[0127] Esters can be saponified, for example, using acetic acid or using NaOH or KOH in water, water/THF or water/dioxane at temperatures between 0 and 100°.

[0128] Furthermore, free amino groups can be acylated in a conventional manner using an acid chloride or anhydride or alkylated using an unsubstituted or substituted alkyl halide, advantageously in an inert solvent, such as dichloromethane or THF, and/or in the presence of a base, such as triethylamine or pyridine, at temperatures between −60 and +30°.

[0129] A base of the formula I can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as ethanol, followed by evaporation. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and/or purification of the compounds of the formula I.

[0130] On the other hand, compounds of the formula I can be converted into the corresponding metal salts, in particular alkali metal or alkaline earth metal salts, or into the corresponding ammonium salts using bases (for example sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate). It is also possible to use physiologically acceptable organic bases, such as, for example, ethanolamine.

[0131] Compounds of the formula I according to the invention may be chiral owing to their molecular structure and may accordingly occur in various enantiomeric forms. They can therefore exist in racemic or in optically active form.

[0132] Since the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or even the intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even employed as such in the synthesis.

[0133] In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (for example N-benzoylproline) or N-benzenesulfonylproline), or the various optically active camphorsulfonic acids. Also advantage is chromatographic enantiomer resolution with the aid of an optically active resolving agent (for example dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or chirally derivatized methacrylate polymers immobilized on silica gel). Examples of suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.

[0134] The invention furthermore relates to the use of compounds of the formula I and/or their physiologically acceptable salts for the preparation of pharmaceutical preparations, in particular by non-chemical methods. They can be converted here into a suitable dosage form together with at least one solid, liquid and/or semiliquid excipient or assistant and, if desired, in combination with one or more further active ingredients.

[0135] The invention thus also relates to pharmaceutical preparations comprising at least one medicament according to one of claims 5 and 6 and, if desired, excipients and/or assistants and, if desired, other active ingredients.

[0136] These preparations can be used as medicaments in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral or topical administration and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates, such as lactose or starch, magnesium stearate, talc or vaseline. Suitable for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal administration are suppositories, suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, furthermore suspensions, emulsions or implants, and suitable for topical application are ointments, creams or powders. The novel compounds may also be lyophilised and the resultant lyophilisates used, for example, to prepare injection preparations. The preparations indicated may be sterilized and/or comprise assistants, such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifying agents, salts for modifying the osmotic pressure, buffer substances, colorants and flavours and/or a plurality of further active ingredients, for example one or more vitamins.

[0137] The invention also relates to the use of compounds according to claims 1 and 2 and/or their physiologically acceptable salts for the preparation of a medicament for combating thromboembolic illnesses, such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.

[0138] In general, the substances according to the invention are preferably administered in doses between about 1 and 500 mg, in particular between 5 and 100 mg, per dosage unit. The daily dose is preferably between about 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and method of administration, on the excretion rate, medicament combination and severity of the particular illness to which the therapy applies. Oral administration is preferred.

[0139] Above and below, all temperatures are given in ° C. In the following examples, ‘conventional work-up’ means that water is added if necessary, the pH is adjusted, if necessary, to between 2 and 10, depending on the constitution of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallization. Rf values on silica gel; eluent: ethyl acetate/methanol 9:1.

[0140] Mass spectrometry (MS): EI (electron ionisation) M⁺

[0141] FAB (fast atom bombardment) (M+H)⁺

EXAMPLE 1

[0142] Preparation of Starting Materials of the Formula II

[0143] 1.1

[0144]10 ml of triethylamine are added to a solution of 4.6 ml of n-propylamine in 100 ml of THF. 8.5 ml of trifluoroacetic anhydride are subsequently added dropwise. The mixture is stirred for 4 hours and subjected to conventional work-up, giving 5.58 g of N-propyl-2,2,2-trifluoroacetamide (“AA”) as a yellow oil, EI 155.

[0145] 1.2

[0146] 13.0 g of caesium carbonate are added to a solution of 5.0 g of “AA” in 200 ml of DMF, and the mixture is stirred at RT for 0.5 hour. 10.0 g of 3-[3-bromomethyl)phenyl]-5-methyl-1,2,4-oxadiazole [preparation see Mederski WWKR et al., Tetrahedron 1999, 55, 12757] are added dropwise, and the mixture is stirred for a further 18 hours. Conventional work-up gives 9.32 g of 2,2,2-trifluoro-N-[3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-N-propylacetamide (“AB”) as a yellow oil, FAB 328.

[0147] 1.3

[0148] 1.9 g of lithium hydroxide and 15 ml of water are added to a solution of 8.5 g of “AB” in 300 ml of methanol, and the mixture is refluxed with stirring for a further 2.5 hours. Conventional work-up gives 4.51 g of [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propylamine (“AC”) as a yellow oil, FAB 232.

[0149] 1.4

[0150] 1.1 g of 4-bromophenyl chloroformate and 1.8 g of polymeric DMAP are added to a solution of 0.82 g of “AC” in 50 ml of dichloromethane, and the mixture is stirred at RT for 16 hours. Conventional work-up gives 1.53 g of 4-bromophenyl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propylcarbamate (“AD”), EI 430.

EXAMPLE 2

[0151] 2.1

[0152] 1.0 g of 2-(tert-butylaminosulfonyl)phenylboronic acid, 8.0 ml of 2M sodium carbonate solution and 75 mg of PdCl₂(dppf) are added successively to a solution of 0.7 g of “AD” in 40 ml of ethylene glycol dimethyl ether, and the mixture is stirred at 85° for 1.5 hours. Conventional work-up gives 0.65 g of 2′-tert-butylaminosulfonylbiphenyl-4-yl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propylcarbamate (“AE”), m.p. 122-123°, EI 562.

[0153] 2.2

[0154] 0.5 ml of acetic acid is added to a solution of 0.51 g of “AE” in 25 ml of methanol, 2.0 g of Raney nickel (water-moist) are added, and the mixture is stirred under a hydrogen atmosphere for 18 hours. The catalyst is separated off, and conventional work-up gives 0.43 g of 2′-tert-butylaminosulfonylbiphenyl4-yl (3-amidinobenzyl)propylcarbamate (“AF”), FAB 523.

[0155] 2.3

[0156] A solution of 0.35 g of “AF” in 3.5 ml of TFA and 0.35 ml of anisole is stirred at RT for 16 hours. Conventional work-up gives 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)propylcarbamate, m.p. 119-120°, FAB 467. Affinity to receptors: IC₅₀ values [nM/litre] IC₅₀ (factor Xa, human) = 450.0 IC₅₀ (TF/VIIa) = 350.0

[0157] The following compounds are obtained analogously

[0158] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)methylcarbamate,

[0159] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)ethylcarbamate,

[0160] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)isopropylcarbamate,

[0161] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)butylcarbamate,

[0162] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)isobutylcarbamate,

[0163] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)pentylcarbamate,

[0164] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)-sec-butylcarbamate,

[0165] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)cyclohexylmethylcarbamate,

[0166] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)benzylcarbamate.

EXAMPLE 3

[0167] 3.1 Analogously to Example 2.1, 0.7 g of “AD” and 0.4 g of 2-(methylthio)phenylboronic acid give 0.63 g of 2′-methylthiobiphenyl-4-yl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propylcarbamate (“AG”) as a yellow resin, EI 473.

[0168] 3.2 A suspension of 0.56 g of “AG” and 0.9 g of sodium perborate trihydrate in 30 ml of acetic acid is stirred at RT for 36 hours. Conventional work-up gives 0.415 g of 2′-methylsulfonylbiphenyl-4-yl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]propylcarbamate (“AH”), m.p. 50-51°, EI 505.

[0169] 3.3 Analogously to Example 2.2, 0.3 g of “AH” gives 0.255 g of 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)propylcarbamate FAB 466. Affinity to receptors: IC₅₀ values [nM/litre] IC₅₀ (factor Xa, human) = 340.0 IC₅₀ (TF/VIIa) = 130.0

[0170] The following compounds are obtained analogously:

[0171] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)methylcarbamate,

[0172] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)ethylcarbamate,

[0173] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)isopropylcarbamate,

[0174] 2′-methylsulfonylbiphenyl-4-yl (3-amid inobenzyl)butylcarbamate,

[0175] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)isobutylcarbamate,

[0176] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)pentylcarbamate,

[0177] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)-sec-butylcarbamate,

[0178] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)cyclohexylmethylcarbamate,

[0179] 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)benzylcarbamate.

EXAMPLE 4

[0180] The reactions described in this example are carried out analogously to the procedure of S. M. Rahmathullah et al. in J. Med. Chem. 1999, 42, 3994-4000. The corresponding acid chlorides are firstly derivatised to give the 4-nitrophenylcarbonate compounds, which are then reacted further with the amidino compounds.

[0181] Starting from methyl chloroformate and reaction of the following “amidino compounds”:

[0182] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)propylcarbamate,

[0183] 2′-aminosulfonylbiphenyl-4-yl (3-amid inobenzyl) methylcarbamate,

[0184] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)ethylcarbamate,

[0185] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)isopropylcarbamate,

[0186] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)butylcarbamate,

[0187] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)isobutylcarbamate,

[0188] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)pentylcarbamate,

[0189] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)-sec-butylcarbamate,

[0190] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)cyclohexylmethylcarbamate,

[0191] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)benzylcarbamate gives

[0192] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-propylcarbamate,

[0193] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-methylcarbamate,

[0194] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-ethylcarbamate,

[0195] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-isopropylcarbamate,

[0196] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-butylcarbamate,

[0197] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-isobutylcarbamate,

[0198] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-pentylcarbamate,

[0199] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-sec-butylcarbamate,

[0200] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-cyclohexylmethylcarbamate,

[0201] 2′-aminosulfonylbiphenyl-4-yl [3-(N-methoxycarbonylamidino)benzyl]-benzylcarbamate.

[0202] Starting from thioethyl chloroformate and reaction of the “amidino compounds” gives

[0203] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)benzyl]-propylcarbamate,

[0204] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]methylcarbamate,

[0205] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]ethylcarbamate,

[0206] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]isopropylcarbamate,

[0207] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]butylcarbamate,

[0208] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]isobutylcarbamate,

[0209] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]pentylcarbamate,

[0210] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]sec-butylcarbamate,

[0211] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]cyclohexylmethylcarbamate,

[0212] 2′-aminosulfonylbiphenyl-4-yl [3-(N-ethylthiocarbonylamidino)-benzyl]benzylcarbamate.

[0213] Starting from 2,2,2-trichloroethyl chloroformate and reaction of the “amidino compounds” gives

[0214] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]propylcarbamate,

[0215] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]methylcarbamate,

[0216] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]ethylcarbamate,

[0217] 2′-aminosulfonylbiphenyl-4-yi [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]isopropylcarbamate,

[0218] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]butylcarbamate,

[0219] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]isobutylcarbamate,

[0220] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]pentylcarbamate,

[0221] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]sec-butylcarbamate,

[0222] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]cyclohexylmethylcarbamate,

[0223] 2′-aminosulfonylbiphenyl-4-yl [3-(N-2,2,2-trichloroethoxycarbonyl-amidino)benzyl]benzylcarbamate.

[0224] Starting from benzyl chloroformate and reaction of the “amidino compounds” gives

[0225] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]propylcarbamate,

[0226] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]methylcarbamate,

[0227] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]ethylcarbamate,

[0228] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]isopropylcarbamate,

[0229] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]butylcarbamate,

[0230] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]isobutylcarbamate,

[0231] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]pentylcarbamate,

[0232] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]sec-butylcarbamate,

[0233] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]cyclohexylmethylcarbamate,

[0234] 2′-aminosulfonylbiphenyl-4-yl [3-(N-benzyloxycarbonylamidino)-benzyl]benzylcarbamate.

[0235] Starting from phenyl chloroformate and reaction of the “amidino compounds” gives

[0236] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)benzyl]-propylcarbamate,

[0237] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]methylcarbamate,

[0238] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]ethylcarbamate,

[0239] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]isopropylcarbamate,

[0240] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]butylcarbamate,

[0241] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]isobutylcarbamate,

[0242] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]pentylcarbamate,

[0243] 2′-aminosulfonylbiphenyl-4-yi [3-(N-phenoxycarbonylamidino)-benzyl]sec-butylcarbamate,

[0244] 2′-aminosulfonylbiphenyl-4-yl [3-(N-phenoxycarbonylamidino)-benzyl]cyclohexylmethylcarbamate,

[0245] 2′-aminosulfonylbiphenyl-4-yi [3-(N-phenoxycarbonylamidino)-benzyl]benzylcarbamate.

[0246] Starting from 4-fluorophenyl chloroformate and reaction of the “amidino compounds” gives

[0247] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]propylcarbamate,

[0248] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)-benzyl]methylcarbamate,

[0249] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]ethylcarbamate,

[0250] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]isopropylcarbamate,

[0251] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]butylcarbamate,

[0252] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]isobutylcarbamate,

[0253] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]pentylcarbamate,

[0254] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]sec-butylcarbamate,

[0255] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]cyclohexylmethylcarbamate,

[0256] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-fluorophenoxycarbonylamidino)benzyl]benzylcarbamate.

[0257] Starting from thio-4-methoxyphenyl chloroformate and reaction of the “amidino compounds” gives

[0258] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]propylcarbamate,

[0259] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]methylcarbamate,

[0260] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]ethylcarbamate,

[0261] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]isopropylcarbamate,

[0262] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]butylcarbamate,

[0263] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]isobutylcarbamate,

[0264] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]pentylcarbamate,

[0265] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]sec-butylcarbamate,

[0266] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]cyclohexylmethylcarbamate,

[0267] 2′-aminosulfonylbiphenyl-4-yl [3-(N-4-methoxyphenylthiocarbonylamidino)benzyl]benzylcarbamate.

[0268] Reaction of the “amidino compounds” with 1-acetoxyethyl 4-nitrophenylcarbamate gives

[0269] 2′-aminosulfonylbiphenyl-4-yi [3-(N-acetoxyethoxycarbonylamidino)-benzyl]propylcarbamate,

[0270] 2′-aminosulfonylbiphenyl-4-yi [3-(N-acetoxyethoxycarbonylamidino)-benzyl]methylcarbamate,

[0271] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]ethylcarbamate,

[0272] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]isopropylcarbamate,

[0273] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]butylcarbamate,

[0274] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]isobutylcarbamate,

[0275] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]pentylcarbamate,

[0276] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]-sec-butylcarbamate,

[0277] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]cyclohexylmethylcarbamate,

[0278] 2′-aminosulfonylbiphenyl-4-yl [3-(N-acetoxyethoxycarbonylamidino)-benzyl]benzylcarbamate.

EXAMPLE 5

[0279] The reaction is carried out analogously to S. M. Rahmathullah et al. in J. Med. Chem. 1999, 42, 3994-4000.

[0280] Reaction of ethyl chloroformate and the following “N-hydroxyamidino compounds”:

[0281] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)propylcarbamate,

[0282] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)methylcarbamate,

[0283] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)ethylcarbamate,

[0284] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)isopropylcarbamate,

[0285] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)butylcarbamate,

[0286] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)isobutylcarbamate,

[0287] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)pentylcarbamate,

[0288] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)-sec-butylcarbamate,

[0289] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)cyclohexylmethylcarbamate,

[0290] 2′-aminosulfonylbiphenyl-4-yl (3-N-hydroxyamidinobenzyl)benzylcarbamate

[0291] gives

[0292] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidinobenzyl)-propylcarbamate,

[0293] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)methylcarbamate,

[0294] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidinobenzyl)-ethylcarbamate,

[0295] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)isopropylcarbamate,

[0296] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)butylcarbamate,

[0297] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)isobutylcarbamate,

[0298] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)pentylcarbamate,

[0299] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidinobenzyl)-sec-butylcarbamate,

[0300] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)cyclohexylmethylcarbamate,

[0301] 2′-aminosulfonylbiphenyl-4-yl (3-N-ethoxycarbonyloxyamidino-benzyl)benzylcarbamate.

EXAMPLE 6

[0302] The following compounds are obtained analogously to Example 4: 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)-amidinobenzyl]propylcarbamate,

[0303] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]methylcarbamate,

[0304] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]ethylcarbamate,

[0305] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]isopropylcarbamate,

[0306] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]butylcarbamate,

[0307] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]isobutylcarbamate,

[0308] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]pentylcarbamate,

[0309] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]sec-butylcarbamate,

[0310] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]cyclohexylmethylcarbamate,

[0311] 2′-aminosulfonylbiphenyl-4-yl [3-N—(N,N-diethylaminoethoxycarbonyl)amidinobenzyl]benzylcarbamate,

[0312] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]propylcarbamate,

[0313] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]methylcarbamate,

[0314] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]ethylcarbamate,

[0315] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]isopropylcarbamate,

[0316] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]butylcarbamate,

[0317] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]isobutylcarbamate,

[0318] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]pentylcarbamate,

[0319] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]sec-butylcarbamate,

[0320] 2′-aminosulfonylbiphenyl-4-yl [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]cyclohexylmethylcarbamate,

[0321] 2′-aminosulfonylbiphenyl-4-yi [3-N-(N-methylpiperidin-4-yloxycarbonyl)amidinobenzyl]benzylcarbamate,

[0322] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyridin-2-ylethoxycarbonyl)-amidinobenzyl]propylcarbamate,

[0323] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyrid in-2-ylethoxycarbonyl)-amidinobenzyl]methylcarbamate,

[0324] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyridin-2-ylethoxycarbonyl)-amidinobenzyl]ethylcarbamate,

[0325] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyridin-2-ylethoxycarbonyl)-amidinobenzyl]isopropylcarbamate,

[0326] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyridin-2-ylethoxycarbonyl)-amidinobenzyl]butylcarbamate,

[0327] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyrid in-2-ylethoxycarbonyl)-amidinobenzyl]isobutylcarbamate,

[0328] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyridin-2-ylethoxycarbonyl)-amidinobenzyl]pentylcarbamate,

[0329] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyrid in-2-ylethoxycarbonyl)-amidinobenzyl]sec-butylcarbamate,

[0330] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyrid i n-2-ylethoxycarbonyl)-amidinobenzyl]cyclohexylmethylcarbamate,

[0331] 2′-aminosulfonylbiphenyl-4-yl [3-N-(pyridin-2-ylethoxycarbonyl)-amidinobenzyl]benzylcarbamate.

EXAMPLE 7

[0332] Preparation of 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)(1-methyl-tetrazol-5-ylethyl)carbamate:

[0333] The compound 4-bromophenyl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-(2-cyanoethyl)carbamate (“BA”) is obtained analogously to the preparation of “AD”.

[0334] The compound 2′-tert-butylaminosulfonylbiphenyl-4-yl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl](2-cyanoethyl)carbamate (“BB”)

[0335] is obtained from “BA” analogously to the preparation of “AE”.

[0336] The conversion of the cyano group into the 1H-tetrazol-5-yl group is carried out by conventional processes by reaction with sodium azide or trimethylsilyl azide, giving 2′-tert-butylaminosulfonylbiphenyl-4-yl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl][2-(1H-tetrazol-5-yl)ethyl]carbamate (“BC”).

[0337] Methylation of “BC” using methyl iodide followed by hydrogenation in methanol/acetic acid with Raney nickel catalysis, removal of the catalyst and conventional work-up gives the compound

[0338] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)(1-methyltetrazol-5-ylethyl)carbamate.

[0339] The compound 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)(1-methyltetrazol-5-ylethyl)carbamate is obtained analogously.

EXAMPLE 8

[0340] The compound 4-bromophenyl [3-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl] (ethoxycarbonylmethyl)carbamate (“CC”) is obtained analogously to the preparation of “AD”. The compound 2′-tert-butylaminosulfonylbiphenyl-4-yl (3-amidinobenzyl)(ethoxycarbonylmethyl)carbamate is obtained from “CC” analogously to the preparation of the compounds “AE” and “AF”, and, after the removal of the tert-butyl group, is converted into

[0341] 2′-aminosulfonylbiphenyl-4-yi (3-amidinobenzyl) (ethoxycarbonylmethyl)carbamate.

[0342] The compound

[0343] 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl) (ethoxycarbonylethyl)carbamate is obtained analogously.

EXAMPLE 9

[0344] The following compounds are obtained analogously to Examples 1 and 2:

[0345]2′-aminosulfonyl-biphenyl-4-yl (3-amid inobenzyl)(methoxyethyl)-carbamate,

[0346] 2′-aminosulfonyl-biphenyl-4-yl (3-amidinobenzyl)(methoxymethyl)-carbamate and

[0347] 2′-aminosulfonyl-biphenyl-4-yl (3-amidinobenzyl)(methoxybutyl)-carbamate.

[0348] The examples below relate to pharmaceutical preparations:

EXAMPLE A: INJECTION VIALS

[0349] A solution of 100 g of an active ingredient of the formula 1 and 5 g of disodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilised under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

EXAMPLE B: SUPPOSITORIES

[0350] A mixture of 20 g of an active ingredient of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into moulds and allowed to cool. Each suppository contains 20 mg of active ingredient.

EXAMPLE C: SOLUTION

[0351] A solution is prepared from 1 g of an active ingredient of the formula 1, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄ .12H₂O and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is adjusted to 6.8, and the solution is made up to 1 l and sterilised by irradiation. This solution can be used in the form of eye drops.

EXAMPLE D: OINTMENT

[0352] 500 mg of an active ingredient of the formula I are mixed with 99.5 g of Vaseline under aseptic conditions.

EXAMPLE E: TABLETS

[0353] A mixture of 1 kg of active ingredient of the formula 1, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet contains 10 mg of active ingredient.

EXAMPLE F: COATED TABLETS

[0354] Tablets are pressed analogously to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

EXAMPLE G: CAPSULES

[0355] 2 kg of active ingredient of the formula I are introduced into hard gelatine capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ingredient.

EXAMPLE H: AMPOULES

[0356] A solution of 1 kg of active ingredient of the formula I in 60 l of bidistilled water is sterile filtered, transferred into ampoules, lyophilised under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient. 

1. Compounds of the formula I

in which R is —CO—N═C(NH₂)₂, —NH—C(═NH)—NH₂ or —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —OCOO(CH₂)_(n)NAA′, —COO(CH₂)NAA′, —OCOO(CH₂)_(m)-Het, —COO(CH₂)_(m)-Het, —CO—CAA′-R³, —COO—CAA′-R³, COOA, COSA, COOAr or COOAr′ or by a conventional amino-protecting group,

R′ is unbranched, branched or cyclic alkyl having 1-20 carbon atoms, in which one or two CH₂ groups may be replaced by O or S atoms, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by S(O)_(p)A, S(O)_(p)NHA, CF₃, COOA, CH₂NHA, CN or OA, R³ is —C(Hal)₃, —O(C═O)A or

Ar is phenyl or naphthyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by A, OA, NAA′, NO₂, CF₃, CN, Hal, NHCOA, COOA, CONAA′, S(O)_(p)A or S(O)_(p)NAA′, Ar′ is —(CH₂)_(n)-Ar, A and A′ are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-20 carbon atoms, Het is a monocyclic or bicyclic, saturated, unsaturated or aromatic heterocyclic radical having 1 to 4 N, O and/or S atoms, bonded via N or C, which may be unsubstituted or substituted by A, X is —(CH₂)_(n)—Y, Y is COOA or

Hal is F, Cl, Br or 1, m is 0 or 1, n is 1, 2, 3, 4, 5 or 6, and p 0, 1 or 2, and their pharmaceutically tolerated salts and solvates.
 2. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

and their pharmaceutically tolerated salts and solvates.
 3. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R′ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, and their pharmaceutically tolerated salts and solvates.
 4. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA, and their pharmaceutically tolerated salts and solvates.
 5. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA, R³ is —CCl₃ or —O(C═O)A, and their pharmaceutically tolerated salts and solvates.
 6. Compounds according to claim 1, in which R is C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA, R³ is —CCl₃ or —O(C═O)A, Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂, and their pharmaceutically tolerated salts and solvates.
 7. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(C H₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA, R³ is —CCl₃ or —O(C═O)A, Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂H₂, Ar′ is benzyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by fluorine, and their pharmaceutically tolerated salts and solvates.
 8. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA′-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA, R³ is —CCl₃ or —O(C═O)A, Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂, Ar′ is benzyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by fluorine, A and A′ are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-8 carbon atoms, and their pharmaceutically tolerated salts and solvates.
 9. Compounds according to claim 1, in which R is —C(═NH)—NH₂, which may also be monosubstituted by OH, —OCOOA, —COO(CH₂)_(n)NAA′, —COO(CH₂)_(m)-Het, —COO—CAA—-R³, COOA, COSA, COOAr, COOAr′ or a conventional amino-protecting group,

R¹ is unbranched, branched or cyclic alkyl having 1-8 carbon atoms, in which one CH₂ group may be replaced by O, or is Ar, Ar′ or X, R² is phenyl which is monosubstituted by SO₂A, SO₂NHA, CF₃, COOA, CH₂NHA, CN or OA, R³ is —CCl₃ or —O(C═O)A, Ar is phenyl which is unsubstituted or monosubstituted by A, OA, CF₃, Hal or SO₂NH₂, Ar′ is benzyl which is unsubstituted or monosubstituted, disubstituted or trisubstituted by fluorine, A and A′ are each, independently of one another, H or unbranched, branched or cyclic alkyl having 1-8 carbon atoms, Het is a monocyclic saturated or aromatic heterocyclic radical having 1 or 2 N and/or O atoms, and their pharmaceutically tolerated salts and solvates.
 10. Compounds according to claim 1: a) 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)propylcarbamate, b) 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)propylcarbamate, c) 2′-methylsulfonylbiphenyl-4-yl (3-amidinobenzyl)phenylcarbamate, d) 2′-aminosulfonylbiphenyl-4-yl (3-amidinobenzyl)phenylcarbamate, 35 and their pharmaceutically tolerated salts and solvates.
 11. Process for the preparation of compounds of the formula I according to claim 1 which R is amidino, and their salts, characterized in that a) they are liberated from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent and/or b) a base or acid of the formula I is converted into one of its salts.
 12. Compounds of the formula I according to claims 1 to 10 and their physiologically acceptable salts and solvates as medicament active ingredients.
 13. Medicament active ingredients according to claim 12 as inhibitors of coagulation factor Xa.
 14. Medicament active ingredients according to claim 12 as inhibitors of coagulation factor VI la.
 15. Medicament active ingredients according to claims 12-14 for the treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens.
 16. Pharmaceutical preparation comprising at least one medicament active ingredient according to one of claims 12 to 14 and, if desired, excipients and/or assistants and, if desired, other active ingredients.
 17. Use of compounds according to one or more of claims 1 to 10 and/or their physiologically acceptable salts for the preparation of a medicament for combating illnesses.
 18. Use according to claim 17 for the preparation of a medicament for combating thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosis after angioplasty and claudicatio intermittens. 